Calorie restriction

Calorie restriction, or caloric restriction (CR), aims to improve health and slow the aging process by limiting dietary energy intake. Calorie restriction is a common measure, found in several dietary regimens, including the Okinawa diet [The Anti-Aging Plan: Strategies and Recipes for Extending Your Healthy Years by Roy Walford (page 26)] and the CRON-diet.

Effects on humans

In human subjects, CR has been shown to lower cholesterol, fasting glucose, and blood pressure.Fact|date=May 2008 SomeWho|date=May 2008 consider these to be biomarkers of aging, since there is a correlation between these markers and risk of diseases associated with aging. Except for houseflies (below), animal species tested with CR so far, including primates, rats, mice, spiders, "Drosophila", "C. elegans" and rotifers, have shown lifespan extension Fact|date=June 2007. CR is the only known dietary measure capable of extending maximum lifespanFact|date=February 2008, as opposed to average lifespan. In CR, energy intake is minimized, but sufficient quantities of vitamins, minerals and other important nutrients must be eaten.

A small-scale study in the US at the Washington University School of Medicine in St. Louis studied the effects following a calorie-restricted diet of 10-25% less calorie intake than the average Western diet. Body mass index (BMI) was significantly lower in the calorie-restricted group when compared with the matched group; 19.6 compared with 25.9. The BMI values for the comparison group are similar to the mean BMI values for middle-aged people in the US.

All those on calorie-restricted diets experienced reductions in BMI after starting their diet. Their BMIs decreased from an average of 24 (range of 29.6 to 19.4) to an average of 19.5 (range of 22.8 to 16.5) over the course of their dieting (3-15 years). Nearly all the decrease in BMI occurred in the first year of dieting. It was found that the average total cholesterol and LDL (bad) cholesterol levels for calorie-restricted individuals were the equivalent of those found in the lowest 10% of normal people in their age group. It was found that the average HDL (good) cholesterol levels for calorie-restricted individuals were very high—in the 85th to 90th percentile range for normal middle-aged US men. These positive changes in calorie-restricted individuals were found to occur mainly in the first year of dieting.

It was found that the calorie-restricted group had remarkably low triglyceride levels. In fact, they were as low as the lowest 5% of Americans in their 20s. This is more remarkable when it is noted that the calorie-restricted individuals were actually aged between 35 and 82 years. Both systolic and diastolicblood pressure levels in calorie-restricted group were remarkably low, about 100/60, values normally found in 10-year-old children. Fasting plasma insulin concentration was 65% lower and fasting plasma glucose concentration was also significantly lower in the calorie-restricted group when compared with the comparison group." The comparison group's statistics aligned approximately with the US national average on the dimensions considered. [http://www.medicalnewstoday.com/articles/7586.php Strict diet lowers heart risk] ] Fasting plasma insulin levels [http://diabetes.diabetesjournals.org/cgi/content/abstract/49/12/2094 A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia] ] and fasting plasma glucose levels [http://www.diabetesselfmanagement.com/articles/Diabetes_Definitions/Fasting_Plasma_Glucose_Test Fasting Plasma Glucose Test] ] are used as tests to predict diabetes. " [The researchers also] found that excessive calorie restriction causes malnutrition and can lead to anemia, muscle wasting, weakness, dizziness, lethargy, fatigue, nausea, diarrhea, constipation, gallstones, irritability and depression. The study was published in the March 2007 issue of the Journal of American Medical Association." [http://www.nbc11.com/health/14278224/detail.html Some Try Calorie Restriction For Long Life] ]

Research history

In 1934, Mary Crowell and Clive McCay of Cornell University observed that laboratory rats fed a severely reduced calorie diet while maintaining vital nutrient levels resulted in life spans of up to twice as long as otherwise expected. These findings were explored in detail by a series of experiments with mice conducted by Roy Walford and his student Richard Weindruch. In 1986, Weindruch reported that restricting the calorie intake of laboratory mice proportionally increased their life span compared to a group of mice with a normal diet. The calorie-restricted mice also maintained youthful appearances and activity levels longer and showed delays in age-related diseases. The results of the many experiments by Walford and Weindruch were summarized in their book "The Retardation of Aging and Disease by Dietary Restriction" (1988) (ISBN 0-398-05496-7).

The findings have since been accepted and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in humans. In the meantime, many people have independently adopted the practice of calorie restriction in some form.

Trials were set up at Washington University in 2002 and involved about thirty participants. Dr. Luigi Fontana, clinical investigator, says CR practitioners seem to be aging more slowly than the rest of us. "Take systolic blood pressure," he says. "Usually, that rises with age reliably, partly because the arteries are hardening. In my group, mean age is 55, and mean systolic blood pressure is 110: that’s at the level of a 20-year-old."

A study conducted by the Salk Institute for Biological Studies and published in the journal "Nature" in May 2007 determined that the gene PHA-4 is responsible for the longevity behind calorie restriction in animals, with similar results expected in humans.cite newstitle=The gene for longevity, if you're a wormurl=http://abc.net.au/science/news/stories/2007/1913183.htm?healthdate=2007publisher=ABC Newsaccessdate=2007-05-03] The discovery has given hope to the synthesising of future drugs to increase the human lifespan by simulating the effects of calorie restriction. However, MIT biologist Leonard Guarente cautioned that "(treatment) won't be a substitute for a healthy lifestyle. You'll still need to go to the gym".cite newstitle=Longevity gene linked to low-calorie dietsurl=http://www.usatoday.com/news/health/2007-05-02-longevity-gene_N.htmdate=2007publisher=USA Todayaccessdate=2007-05-03]

Seventy years ago, McCay CM, "et al.", discovered that reducing the amount of calories fed to rats nearly doubled their lifespan. For the last seventy years, scientists have proposed hypotheses as to why. Some explanations included reduced cellular divisions, lower metabolism rates, and reduced production of free radicals generated by metabolism.

Yeast and invertebrates

Recently, Harvard professor David A. Sinclair has conducted research that provides a new explanation for the lifespan extension caused by calorie restriction. It involves the activation of a gene called "Sirt1". When "Sirt1" gene activity is increased by genetic manipulation, caloric restriction does not increase it any further. Knocking out the "Sirt1" gene also eliminates any beneficial effect from caloric restriction. Resveratrol has been demonstrated to increase the activity of the "Sirt1" gene the same way caloric restriction does. When resveratrol increased the subject's lifespan, caloric restriction failed to increase it any further. Presently, "Sirt1" gene activity has not been increased in rats by genetic manipulation.

Drosophila

Research in 2003 by Mair "et al." [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=14500985&itool=pubmed_AbstractPlus Demography of dietary restriction and death in Drosophila] ] showed that calorie restriction has instantaneous effects on death rates in fruit flies of any age.

Caenorhabditis elegans

Recent work in Caenorhabditis elegans has shown that restriction of glucose metabolism extends life span by primarily increasing oxidative stress to exert an ultimately increased resistance against oxidative stress, a process called (mito)hormesis.

Why might CR increase longevity?

There have been many theories as to how CR works, and many of them have fallen out of favor or been disproved. These include reduced basal metabolic rate, developmental delay, the control animals being s, and decreased glucocorticoid production.

(Mito)hormesis

A small number of researchers in the CR field are now proponents of a new theory known as the "Hormesis hypothesis of CR" also known as the "Mitohormesis hypothesis of CR" due to the likely involvement of mitochondria. Southam and Ehrlich (1943) reported that a bark extract that was known to inhibit fungal growth, actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein" which means "to excite".

The (Mito)hormesis hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defense response that helps protect it against the causes of aging. In other words, CR places the organism in a defensive state so that it can survive adversity, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).

While the (Mito)hormesis hypothesis of CR was a purely hypothetical concept until late 2007, recent work by Michael Ristow's group in a small worm named Caenorhabditis elegans has shown that restriction of glucose metabolism extends life span by primarily increasing oxidative stress to exert an ultimately increased resistance against oxidative stress. [ [http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002562 Publication demonstrating that oxidative stress is promoting life span] ] This is probably the first experimental evidence for hormesis being an essential cause for extended life span following CR.

Insulin signaling

Early work in C.elegans (see Cynthia Kenyon) and more recent research in mice has suggested (see Matthias Bluher, C. Ronald Kahn, Barbara B. Kahn, "et al.") that it is not only reduced calorie intake which influences longevity. This was done by studying animals which have their metabolism changed to reduce activity of the hormoneinsulin or downstream elements in its signal transduction, consequently retaining the leanness of animals in the earlier studies. It was observed that these animals can have a normal dietary intake, but have a similarly increased lifespan. This suggests that lifespan is increased for an organism if it can remain lean and if it can avoid any excess accumulation of adipose tissue: if this can be done while not diminishing dietary intake (as in some minority eating patterns, see e.g. Living foods diet or Joel Fuhrman) then the 'starvation diet' anticipated as an impossible requirement by earlier researchers is no longer a precondition of increased longevity.

The extent to which these findings may apply to human nutrition and longevity is as noted above under investigation. A paper in the Proceedings of the National Academy of Sciences, U.S.A. in 2003 showed that practitioners of a CR diet had significantly better cardiovascular health (PMID 15096581). Also in progress are the development of CR mimetic interventions.

Gurarente has recently published that behavior associated with caloric restriction did not occur when Sirt1 knockout mice were put on a calorie restricted diet, the implication being that Sirt1 is necessary for mediating the effects of caloric restriction. However, the same paper also reported that the biochemical parameters thought to mediate the lifespan extending effects of calorie restriction (reduced insulin, igf1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-extending effect of CR was still evident in Sirt1 knockout mice was not reported in that study.

DHEA

While calorie restriction has been shown to increase DHEA in primates (PMID 12543259), it has not been shown to increase DHEA in post-pubescent primates (PMID 15247063).

Free radicals and glycation

Two very prominent theories of aging are the free radical theory and the glycation theory, both of which can explain how CR could work. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide. With CR, energy is conserved and there is less free radical generation. A CR organism will be less fat and require less energy to support the weight, which also means that there does not need to be as much glucose in the bloodstream. Less blood glucose means less glycation of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type II Diabetics are people with insulin insensitivity caused by long-term exposure to high blood glucose. Obesity leads to type 2 diabetes. Type 2 diabetes and uncontrolled type 1 diabetes are much like "accelerated aging", due to the above effects. There may even be a continuum between CR and the metabolic syndrome.

In examining Calorie Restriction with Optimal Nutrition, it is observed that with less food, and equal nutritional value, there is a higher ratio of nutrients to calories. This may lead to more ideal essential and beneficial nutrient levels in the body. Many nutrients can exist in excess to their need, without side effects as long as they are in balance and not beyond the body's ability to store and circulate them. Many nutrients serve protective effects as antioxidants, and will be at higher levels in the body as there will be lower levels of free radicals due to the lower food intake.

Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits.

Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be no more than adapting the diet to the body's needs.

Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in years past.

Papers on CR in yeast: dismissing increased respiration

In late 2005 Matt Kaeberlein and Brian Kennedy published two important papers on calorie restriction in yeast. In [http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pgen.0010069.eor the first] , they show that calorie restriction does not increase respiration in yeast (in contrast with the model proposed by Lenny Guarente). In [http://www.sciencemag.org/cgi/content/abstract/310/5751/1193 the second] , calorie restriction decreased the activity of TOR, a nutrient-responsive signaling protein already known to regulate aging in worms and flies. This paper is the first to directly link TOR to calorie restriction.

Papers on CR in C. elegans: promoting increased respiration

In late 2007 Michael Ristow published a paper on calorie restriction in C.elegans. [ [http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002562 Publication demonstrating that oxidative stress is promoting life span] ] Here the authors show that calorie restriction does increase respiration in C.elegans as previously described for yeast (in support of the model proposed by Lenny Guarente, although independent of Sir2.1).

Evolution

It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to upregulate protective and repair enzyme mechanisms to try to ensure that it is fit for reproduction in future years. This seems to be supported by recent work studying hormones. [ [Charlie Rose- Calorie restriction] ]

Objections

No benefit to houseflies

One of the most significant oppositions to caloric restriction comes from Michael Cooper, who has shown that caloric restriction has no benefit in the housefly. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15319362&query_hl=22&itool=pubmed_docsum Effect of caloric restriction on life span of the ... [FASEB J. 2004 - PubMed Result ] ] Michael Cooper claims that the widely purported effects of calorie restriction may be because a diet containing more calories can increase bacterial proliferation, or that the type of high calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.

=Catabolic da

A major conflict with calorie restriction is that adequate calorie intake is needed to prevent catabolizing the body's tissues. A body in a catabolic state promotes the degeneration of muscle tissue, including the heart.

Physical activity testing biases

While some tests of calorie restriction have shown increased muscle tissue in the calorie-restricted test subjects,Fact|date=June 2007 how this has occurred is unknown.Fact|date=June 2007 Muscle tissue grows when stimulated, so it is possible that the calorie-restricted test animals exercised more than their companions on higher calories. The reasons behind this may be that animals enter a foraging state during calorie restriction. In order to control this variable, such tests would need to be monitored to make sure that levels of physical activity are equal between groups.

Insufficient calories and amino acids for exercise

Exercise has also been shown to increase health and lifespan and lower the incidence of several diseases. Calorie restriction comes into conflict with the high calorie needs of athletes, and may not provide them adequate levels of energy or sufficient amino acids for repair, although this is not a criticism of CR per se, since it is certainly possible to be an unhealthy athlete, or an athlete destined to die at a young age due to poor diet, stresses, etc.

Benefits only the young

There is evidence to suggest that the benefit of CR in rats might only be reaped in early years. A study on rats which were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average lifespan of the Ad libitum group. [Lipman RD, Smith DE, Bronson RT, Blumberg J. "Is late-life caloric restriction beneficial?" Aging (Milano). 1995 Apr;7(2):136-9. PMID 7548264] This view, however, is disputed by Spindler, Dhahbi, and colleagues who showed that in late adulthood, acute CR partially or completely reversed age-related alterations of liver, brain and heart proteins and that mice placed on CR at 19 months of age show increases in lifespan. [Spindler SR. Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mech Ageing Dev. 2005 Sep;126(9):960-6. Review. PMID: 15927235]

Possible contraindications

Both animal and human research suggest BUD CR may be contraindicated for people with amyotrophic lateral sclerosis (ALS). Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh "et al" therefore concluded: "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated." [Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA. "Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse." Muscle Nerve. 2005 Feb;31(2):214-20. PMID 15625688.] Hamadeh "et al" also note two human studies [ Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. "Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death." Am J Clin Nutr. 1996 Jan;63(1):130-7. PMID 8604660.] [Slowie LA, Paige MS, Antel JP. "Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS)." J Am Diet Assoc. 1983 Jul;83(1):44-7. PMID 6863783] that they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They go on to conclude: "We conclude that ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake." (PMID 8604660)

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits. [Pedersen WA, Mattson MP. "No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice." Brain Res. 1999 Jun 26;833(1):117-20. PMID 10375685. ] Suggesting that a calorically dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow the progress of disease. [Zhao Z, Lange DJ , Voustianiouk A, "et al." "A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis." [http://www.biomedcentral.com/1471-2202/7/29 BMC Neuroscience 2006, 7:29.] (PMID 16584562). [http://www.sciencedaily.com/releases/2006/04/060417104324.htm Media report on Zhao "et al"] .] More recently, Mattson "et al" opine that the death by ALS of Roy Walford, a pioneer in CR research and its antiaging effects, may have been a result of his own practice of CR. [Mattson MP, Cutler RG, Camandola S. "Energy intake and amyotrophic lateral sclerosis." Neuromolecular Med. 2007;9(1):17-20. PMID 17114821.] However, as Mattson "et al" acknowledge, Walford's single case is an anecdote that by itself is insufficient to establish the proposed cause-effect relation.

Negligible effect on larger organisms

Another objection to CR as an advisable lifestyle for humans is the claim that the physiological mechanisms that determine longevity are very complex, and that the effect would be small to negligible in our species. [Phelan JP, Rose MR. "Why dietary restriction substantially increases longevity in animal models but won't in humans." Ageing Res Rev. 2005 Aug;4(3):339-50. PMID 16046282]

Intermittent fasting as an alternative approach

Studies by Mark P. Mattson, Ph. D., chief of the National Institute on Aging's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting and calorie restriction affect the progression of diseases similar to Huntington's disease, Parkinson's disease, and Alzheimer's disease in mice (PMID 11119686). In one study, rats and mice ate a low-calorie diet or were deprived of food for 24 hours every other day (PMID 12724520). Both methods improved glucose metabolism, increased insulin sensitivity, and increased stress resistance. Researchers have long been aware that calorie restriction extends lifespan, but this study showed that improved glucose metabolism also protects neurons in experimental models of Parkinson's and stroke.

Another NIA study found that intermittent fasting and calorie restriction delays the onset of Huntington's disease-like symptoms in mice and prolongs their lives (PMID 12589027). Huntington's disease (HD), a genetic disorder, results from neuronal degeneration in the striatum. This neurodegeneration results in difficulties with movements that include walking, speaking, eating, and swallowing. People with Huntington's also exhibit an abnormal, diabetes-like metabolism that causes them to lose weight progressively.

This NIA study compared adult HD mice who ate as much as they wanted to HD mice who were kept on an intermittent fasting diet during adulthood. HD mice possess the abnormal human gene huntingtin and exhibit clinical signs of the disease, including abnormal metabolism and neurodegeneration in the striatum. The mice on the fasting program developed clinical signs of the disease about 12 days later and lived 10 to 15% longer than the free-fed mice. The brains of the fasting mice also showed less degeneration. Those on the fasting program also regulated their glucose levels better and did not lose weight as quickly as the other mice. Researchers found that fasting mice had higher brain-derived neurotrophic factor (BDNF) levels. BDNF protects neurons and stimulates their growth. Fasting mice also had high levels of heat-shock protein-70 (Hsp70), which increases cellular resistance to stress.

Another NIA study compared intermittent fasting with cutting calorie intake. Researchers let a control group of mice eat freely (ad libitum). Another group was fed 60% of the calories that the control group consumed. A third group was fasted for 24 hours, then permitted to free-feed. The fasting mice didn't cut total calories at the beginning and the end of the observation period, and only slightly cut calories in between. A fourth group was fed the average daily intake of the fasting mice every day. Both the fasting mice and those on a restricted diet had significantly lower blood sugar and insulin levels than the free-fed controls. Kainic acid, a toxin that damages neurons, was injected into the dorsal hippocampus of all mice. Hippocampal damage is associated with Alzheimer's. Interestingly, the scientists found less damage in the brains of the fasting mice than in those that ate a restricted diet, and most damage in mice with an unrestricted diet. But the control group which ate the average daily intake of the fasting mice also showed less damage than the mice with restricted diet. [R. Michael Anson, Zhihong Guo, Rafael de Cabo, Titilola Iyun, Michelle Rios, Adrienne Hagepanos, Donald K. Ingram, Mark A. LaneDagger, Mark P. Mattson. " [http://www.pnas.org/cgi/content/full/100/10/6216 Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.] " PNAS | May 13, 2003 | vol. 100 | no. 10 | 6216-6220]

*Interview, "I want to live forever", Cynthia Kenyon, Professor of Biochemistry and Biophysics at the University of California, San Francisco, by James Kingsland. New Scientist online, 20 October2003. http://www.newscientist.com/channel/opinion/mg18024175.300

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